1

Graft Sources for Hematopoietic Cell

Transplantation

Dennis L. Confer, MD

Chief Medical Officer, NMDP/Be The Match

Associate Scientific Director, CIBMTR

4/18/2016

The National Marrow Donor Program

1968 First successful related donor transplants

1973 First successful unrelated donor transplant

1979 Laura Graves URD transplant for ALL

1986 NBMDR established

1987 Two transplants completed

Today: World’s largest registry

>14 million donors

>230,000 CBUs

>73,000 Transplants completed

The Success of NMDP is coupled to 29 years of uninterrupted Federal support

2

4/18/2016 3

Simon Bostic, URD Transplant Recipient

4/18/2016

The National Marrow Donor Program

1968 First successful related donor transplants

1973 First successful unrelated donor transplant

1979 Laura Graves URD transplant for ALL

1986 NBMDR established

1987 Two transplants completed

Today: World’s largest registry

>14 million donors

>230,000 CBUs

>73,000 Transplants completed

The Success of NMDP is coupled to 29 years of uninterrupted Federal support

4

4/18/2016

The National Marrow Donor Program

• Non-profit 501(c)3 corporation headquartered in Minneapolis, Minnesota

– 900 employees

– $400 million annual budget

• Contracted to operate the legislatively authorized CW “Bill” Young Cell Transplantation Program

– Four separate contracts – BMCC, CBCC, SPA/OPA and SCTOD

– bloodcell.transplant.hrsa.gov

• branding

– www.bethematch.org

– www.bethematchclinical.org

5 4/18/2016 6

National Marrow Donor Program Adult Donors & Cord

Blood Units – April 10, 2016

0

20000

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1,000,0002,000,0003,000,0004,000,0005,000,0006,000,0007,000,0008,000,0009,000,000

10,000,00011,000,00012,000,00013,000,00014,000,00015,000,000

1988

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2008

2010

2012

2014

2016

2018

Ad

ult

Do

no

rs

Adult Donors

14,199,518

CBUs

231,977 Cord

Blo

od

Un

its

2

4/18/20167

NMDP Transplants Facilitatedby Fiscal Year 1987–2015

>73,000 Total

0

500

1000

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6500

198

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Nu

mb

er

of

Tra

nsp

lan

ts

Year of Transplant

Cord blood

Peripheral blood stem cells

Bone marrow

4/18/2016

Transplants by Recipient Age

Survival After Unrelated Donor TransplantationAge <50 years, myeloablative conditioning, acute leukemia in

remission or MDS

Odds of 1-year survival increased by 8% per year

(95% CI, 7-9%) on average between 1990 and 2011

0

10

20

30

40

50

60

70

80

90

100

Prob

ab

ilit

y, %

Year of Transplant

Adjusted 1-year Overall Survival

Influence of HLA8/8 Match 7/8 Match 6/8 Match

S. Lee, et al. Blood 2007 Showed impact of single

allele mismatch at A, B, C and DRB1

0.0

0.1

0.2

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0.5

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1.0

0 12 24 36 48 60

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0 12 24 36 48 60

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1.0

0 12 24 36 48 60

Surv

ival

Early Disease Stage Intermediate Disease Stage Advanced Disease Stage

Surv

ival

Surv

ival

Months after transplant Months after transplant Months after transplant

Other HLA/Donor Characteristics

Associated with Outcome

• Low-expression HLA alleles (DQ, DP,

DRB3,4,5)

– Permissive versus non-permissive DP

mismatches

– Multiple mismatches

• Donor age - age >50 about equivalent to a

single locus mismatch

• Non-HLA genomics – KIR Phenotype

11

One-year Survival by Year of

Transplant, Donor and Age,

0

20

40

60

80

100

19…

1991

1992

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1998

1999

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2007

2008

2009

2010

2011

HLA-matched siblings, Age < 50 Unrelated donors, Age < 50

Acute Leukemia, CML or MDS early disease status. 12

3

4/18/201613

NMDP Transplants Facilitatedby Fiscal Year 1987–2014

>73,000 Total

0

500

1000

1500

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Nu

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nsp

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ts

Year of Transplant

Cord blood

Peripheral blood stem cells

Bone marrow

BMT CTN Protocol 0201

Results of a Phase III Randomized Multicenter Trial of

HLA compatible Unrelated Donor Transplantation:

G-CSF Mobilized Peripheral Blood Stem Cells (PBSC)

Versus

Bone Marrow

BMT CTN 0201

Study Characteristics

Design: Randomized, multicenter trial.

Primary endpoint: Two-year survival by intent-to-treat.

Randomization: PBSC vs. marrow, 1:1.

Stratification: Transplant center and disease risk.

Accrual: 550 donor-recipient pairs.

Power: 80% to detect a 12.5% difference, alpha 0.05.

Enrollment: March 31st, 2004 to September 9th, 2009.

Analysis: as of November 15th, 2011.

Median follow-up: 36 months

BMT CTN 0201

Overall Survival Disease-free Survival

Analysis after Transplantation

Preplanned subset analyses did not find study arm interaction with:

-Disease Risk

-Donor HLA matching

-Patient Age

Months

100

0

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80

90

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30

50

70

0 12 24 36 06 18 30 12 24 36

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30

50

70

6 18 30

Prob

ab

ilit

y, %

PBSC

Marrow

PBSC

Marrow

2-year point P value = 0.335 2-year point P value = 0.382

BMT CTN 0201

Non-relapse Mortality Relapse

0

100

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40

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80

90

10

30

50

70

36 0 12 24 366 18 300 12 24

100

0

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40

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80

90

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30

50

70

6 18 30

In

cid

en

ce, %

Months

P value = 0.986 P value = 0.735

Marrow

PBSC

Analysis after Transplantation

PBSC

Marrow

BMT CTN 0201

Platelets > 20kNeutrophils

Engraftment after Transplantation

0 14 28 56 0

100

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90

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30

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70

7 21 35 42 49 60 120 180

0

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30 90 150

In

cid

en

ce, %

Days

5 days 7 days

P < 0.001 P < 0.001

Marrow

PBSC PBSC

Marrow

4

BMT CTN 0201

Grades 3-4Grades 2-4

In

cid

en

ce, %

Days

0 60 120 180 0

100

0

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90

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50

70

30 90 150 60 120 180

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90

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30

50

70

30 90 150

PBSC

Marrow

PBSC

Marrow

p-value=0.768 p-value=0.346

Acute Graft-versus-Host Disease (GVHD)

In

cid

en

ce, %

Months

0 24

100

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90

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70

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70

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BMT CTN 0201

Overall Chronic GVHD

Marrow PBSC P value

Chronic Extensive 32% 48% P<0.001

PBSC

Marrow

P value = 0.014

Off therapy at 2 yrs 57% 37% P=0.026

BMT CTN 0201

Summary

Survival is not different after marrow or

PBSC transplants from unrelated donors.

Other outcomes are similar, with the

exception of better engraftment and more

chronic extensive GVHD with PBSC.

Is the shift to greater PBSC use justified?

Patients Without an Adult Donor May be

Helped by Banked Umbilical Cord Blood

Advantages: Immediately available (important for patients

with rapidly progressive diseases)

No risk to donor

Allows more HLA-mismatch with lower risk of GVHD

Disadvantages: Low cell numbers - inadequate cell dose for

many adults, requiring two units (expensive)

Slow hematopoietic recovery and higher risk of graft failure

Cord Blood Transplantation

23

• Multiple studies from individual centers, Eurocord, the NYBC, EBMT and CIBMTR document that Umbilical Cord Blood cells – Can establish durable hematopoiesis

– Have potent graft-versus-tumor effects

– Can lead to successful transplant outcomes in a variety of malignant and non-malignant diseases in adults and children

• Outcomes of UCB transplants have clearly improved over time

2 Year Survival After Cord Blood

Transplants for ALL, AML and MDS

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Children (<16) Adults

1996-99 2000-05 2006-11

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5

Leukemia-free Survival in Children – depends on HLA

Match and Cell Dose: Better, the Same or Slightly Worse

than Matched Bone Marrow (Eapen, Lancet, 2007)

Years

0 1 2 5

Pro

ba

bilit

y,

%

100

0

20

40

60

80

43

CB 1-Ag MM high (n=157), 41%

BM matched (n=369), 40%

CB 1-Ag MM low (n=44), 36%

CB matched (n=35), 60%

CB 2-Ag MM (n=267), 33%

BM MM (n=123), 30%

25

Leukemia-free Survival In AdultsTransplantation in Remission: Slightly worse than Matched

Marrow or Peripheral Blood

Eapen et al; Lancet Oncol 2010

Pro

babili

ty, %

100

0

20

40

60

80

Months 0 6 12 18 24

8/8 BM, 52%

7/8 BM, 41%

8/8 PBPC, 50%

7/8 PBPC 39%

4-6/6 UCB, 44%

Lesser (intermediate resolution A, B; high

resolution DRB1) vs. Allele-level HLA-match

Loci mis-

matched

using

usual

typing

Loci mismatched using high resolution typing

for A, B, C, DRB1

5 4 3 2 1 0

2 11% 31% 49% 10% __ __

1 1% 8% 22% 44% 25% __

0 __ __ 4% 18% 24% 54%

27

Effect of Allele-level Matching at A, B, C, DRB1

on Transplant-related Mortality after Cord

Blood Transplantation

Note very low TRM with

8/8 match

100

0

20

40

60

80

Inc

ide

nc

e,

%

Years

0 1 32

6/8 (26%)

4/8 (37%)

5/8 (34%)

3/8 (41%)

7/8 (26%)

8/8 (9%)

P < 0.001

Likely to change the

paradigm for cord

selection

Eapen et al; Lancet Oncol 2011

Cell Dose

• Major limitation to Cord Blood Transplantation is the small number of cells in each unit

– Slow hematopoietic recovery

– Slow immune recovery

– Graft failure

• Strategies:– Selection of large units

– Double cord transplantation (expensive)

– Expansion and homing techniques (in development, often requires two units)

29

4/18/2016

A Comprehensive Model for

Registry Match Rates

30

N Engl J Med 2014;371:339-48

6

4/18/2016

8/8 match likelihoods by year-end using current donor

availability, extending recruitment trends to 2017

31 4/18/2016 32

4/18/2016

≥ 5/6 CBU match rates for children by year

33

Cell Dose ≥ 2.5 x 10^7 per Kg

4/18/2016

≥ 5/6 CBU match rates for adults by year

34

Cell Dose ≥ 2.5 x 10^7 per Kg

The “New” Alternative – Haploidentical

• In Europe, haploidentical transplants using T-cell depleted peripheral blood grafts have been used for a small but important proportion of transplants

• In the US, very few haploidentical transplants were performed until the last five years

– No approved CD34 selection or T-cell depletion device available

• Introduction of the Johns Hopkins approach using post-transplant cyclophosphamide increased interest

– Technically simple

– Costs similar to HLA-identical sibling transplant

35

Cyclophosphamide-induced tolerance

Proliferating

ALLOREACTIVE

cells are killed

Non-proliferating

non-alloreactive

cells are spared

anti-CMV

anti-HSV

anti-CMV

anti-HSV

7

BMT CTN PROTOCOL #0603A Phase II Trial of Reduced Intensity

Conditioning and Transplantation of Partially

HLA-Mismatched Bone Marrow for Patients

with Hematologic Malignancies

BMT CTN PROTOCOL #0604A Phase II Trial of Reduced Intensity

Conditioning and Transplantation of Umbilical

Cord Blood from Unrelated Donors in Patients

with Hematologic Malignancies

Brunstein, Fuchs, et al Blood 2011

Parallel Designs

• Age ≤ 70

• Diseases

– Leukemia: high risk, in remission

– Lymphoma

• Hodgkin, mantle cell, or large cell: chemosensitive

relapse, not eligible for autologous SCT

• Follicular or marginal zone: multiply relapsed

• Adequate organ function, performance score >60%

• N=50 in each trial

• Primary endpoint: 6-month survival

38

Brunstein, et al 2011 39

AGVHD – 40/25%

CGVHD – 25%

AGVHD – 40/0%

CGVHD – 13%

Comparisons of clinical outcomes:

UCB vs Haplo (BMT CTN 0603/0604)

Months Post Transplant

Prob

ab

ilit

y, %

100

0

20

40

60

80

0 2412 36

68%

54% 54%

52%46%

39%

84%

74%haplo

cord

100

0

20

40

60

80

Months Post Transplant0 2412 36

haplo: 35%

cord: 36%

cord: 38%

haplo: 40%

Overall survival Progression-free survival

Eapen, et al BBMT 2014

Haplo-Identical Transplantations

Hematologic Malignancy

0

20

40

60

80

100

120

140

160

2008 2009 2010 2011 2012 2013

Nu

mb

er

of

Tra

ns

pla

nts

Other centers CTN 0603 centers

Year 0603/0604 paper was

published

Years of 0603/0604 trial

Distribution of Alternative (not an HLA-

matched adult donor) Graft Sources

42

41%

14%

20%

25%

2010N=1646

37%

31%

14%

18%

2014N=1960

Mismunrelated

Haploident

Single Cord

Double Cord

8

0

Pro

ba

bilit

y,

%

Overall Survival Adjusted for age, Disease Risk, secondary AML

Years Years

100

0

20

40

60

80

0 1 32

HR 0.93 (95% CI 0.70 – 1.22), p=0.58

MUD 50% (47-53)

HAPLO 45% (36-54)

Myeloablative

1245 MUD/104 Haplo

0

100

20

40

60

80

1 32

HR 1.06 (95% CI 0.79 – 1.43), p=0.70

HAPLO 46% (35-56)

MUD 44% (40-47)

Reduced Intensity

737 MUD/88 Haplo

Ciurea, et al Blood 2015

Limitation of this Analysis - POWER

COMPARISONS OF 3-Year SURVIVAL

Myeloablative:1245 MUD/104 Haplo

Reduced Intensity:737 MUD/88 Haplo

Point

Estimate

Lower

Bound

Upper

Bound

Point

Estimate

Lower

Bound

Upper

Bound

Matched

Unrelated50% 47% 53% 44% 40% 47%

Haploidentical 45% 36% 54% 46% 35% 56%

44

Some Unknowns About Haplos with

Post-Transplant Cyclophosphamide

• Long-term control of malignancy

• Engraftment/outcomes in non-malignant diseases

• Outcomes in Children

• Suitability of Older Donors – More graft failure

– Clonal hematopoiesis more common with older donors – uncertain significance

– Able to donate bone marrow?

– Question: might results be better using post-transplant Cy with younger mismatched unrelated bone marrow donors with appropriate CMV/KIR status?

45

Summary

• Few patients will lack an acceptable

donor/graft source

• All donor/graft types (8/8 or 7/8 adult, haplo,

cord) produce survival outcomes that, if not

identical, are in the same range

– Maximum differences in survival, compared to 8/8

adult donor, are in the range of 10%-15%

– Outcomes now more driven by patient and

disease factors

46

How Universal Donor Availability Might

Change Things

• HCT more likely to impact treatment of a disease since it is available to more people

• Choice of donor/graft will depend on factors other than HLA

– Availability

– Other donor characteristics: age, CMV status, etc.

– Disease recurrence risk

– Infection risk

– Planned conditioning regimen

– Cost

47

Relative risks and benefits of different

cell sources: acquisition issues

UD Cord Haplo

Suitable HLA match

available

90% Caucasian

Much lower for

other ancestries

Increased

chance

(especially rarer

tissue types)

Usually, but

other donor

characteristics

might not be

optimal

Availability Variable

Donor attrition

Predictable Generally

predictable

Speed of acquisition Medium Fast Fast

Cell dose Predictable Low High

Second

donations/DLI

Possible Not possible Possible

Cost Higher than

sibling

Much higher Equal to

sibling

9

Relative risks and benefits of different

cell sources: clinical outcomes

UD Cord Haplo*

Engraftment Fast Slow Fast

Graft failure Rare More common Slightly more

common

GvHD High (esp with

mismatch)

Lower than

expected with

mismatch

Low due to

techniques used

Relapse Possibly lower

than sibling

Possibly lower

than sibling

Higher

* In adults with malignancy

A Side Note: Implications of Better

Chronic GVHD Prevention

• Possible with both CD34 selection and

post-transplant cyclophosphamide in both

myeloablative and reduced intensity settings

• Makes allogeneic transplantation more

attractive for non-malignant diseases such as

– Sickle cell disease

– Inborn errors of metabolism

– Lower risk MDS

50

Conclusions

• HCT as a therapy should be considered early based on relative efficacy/toxicity compared to non-HCT therapy – not donor availability– Timing should be optimized

• Randomized comparisons (rather than biologic assignment, ie., donor vs no donor) of HCT vs non-HCT therapy are now possible in many situations, particularly in adults with hematologic malignancies, and should be pursued

51

Thank You!

52